Your Digest for Wednesday, Dec 20, 2023 10:59 AM


EffectsOfAldosterone.png


old test was urinary 5-hydroxyindoleacetic acid.


Hormone secreting cells in the pituitary are acidophils and basophils. Acidophils are somatotrophs and lactotrophs.

IGF has the longer half life; therefore it's used as a screening test for acromegaly. GH has a short half life and levels fluctuate throughout the day so it's not the first test in screening.




### Summary of enzymes involved


  1. Erythrocytosis (Differentiating factor from other haematologic neoplastic diseases is increased red cell mass)

Caused by rickettsia : obligate intracellular gram -ve bacteria with varying morphology

Note: Ticks Vs. fleas : ticks are much larger and have eight legs. Ticks aren't involved in typhus.
Chiggers aren't insects. They are mites.

Epidemic typhus causes the most severe clinical presentation -> severe epidemic typhus may develop gangrene, leading to a loss of digits, limbs, or other appendage.


- Thrombosis: **renal vein thrombosis is a recognised complication of nephrotic syndrome** (occuring in 33%)

[!INFO] Presentation of renal vein thrombosis:

  1. 📑IgA📑It causes recurring episodes of microscopic or gross haematuria lasting a few days. Usually recurs every few months after the onset.
  2. Begins with haematuria 1-2 days after non specific upper respiratory tract infection.

[!INFO] 95% of TTP is immune mediated
Only a tiny percetage is hereditary.

Mnemonic; Transfer

  1. Thrombocytopaenia
  2. schistocytic anaemia
  3. renal impairment

6. immunosuppresion
7. neurology - uraemai -> CNS depression,  ⬇ seizure threshold, asterexis, tremmor, myoglonus, axiety + depression, impaired cognition
    1. Autonomic dysfunction : increased cirulating catecholamines -> alpha receptor down regulation. 
    2. Peripheral - median nerve compression due to Beta 2 microglobulin amyloidosis. 
    3. Advaned uraemia -> symmetrical polyneuropathy.

Immunosuppression in CKD

Clinical implications

Pathogenesis

Source


- They are peptides *similar in structure to insulin* and are **produced in the liver.**
- **IGF-I peaks in puberty** and it's main role is skeletal and cartilage growth. It is stimulated by GH.

However, crystals can precipitate and cause nephropathy. Prevented by adequate hydration.
Neurotoxicity is rare bu[[]]t can cause delirium, tremors, hallucinations and if severe delerium and coma.
Pan-systolic - ventricle leaks to a lower pressure chamber or vessels - MR, TR, VSD

Types of diastolic murmurs

Mid diastolic

Mid diastolic - MS, TS,




Enzyme pathways

CYP2D6 and CYP3A4 are hepatic drug metabolism pathways / enzymes

First pass metabolism

#2019BSQ-OCT/Q14

"The first pass effect is a phenomenon in which a drug gets metabolized at a specific location in the body that results in a reduced concentration of the active drug upon reaching its site of action or the systemic circulation." Basically 👇🏽

First pass effect - drug gets metabolized at a non target organ so that affective dose at the target organ is reduced. Commonest site for this to happen is the liver.

P-glycoproteins in the gut can cause efflux of drugs, reducing absorption. Another example of first pass effect.

First pass metabolism varies between people.
First pass effect is significant only if the liver metabolizes the drug rapidly.
So even though the following are completely eleminated by the liver, since the rate of elimination is low, first pass effect is not significant
e.g. for diazepam, phenytoin, theophylline, warfarin.

In cirrhosis, first pass metabolism is reduced because of

  1. Reduced hepatic function
  2. Blood bypassing the liver due to portosystemic shunting

Drugs with high first pass metabolism:

Effects of having high first pass metabolism

📑More drugs with high FP metabolism:

  1. buspirone,
  2. atorvastatin,
  3. cyclosporine,
  4. felodipine,
  5. 📑midazolam,
  6. 📑nifedipine,
  7. 📑propranolol
  8. alprenolol,
  9. 5-fluorouracil,
  10. 📑 morphine,
  11. pentazocine, and
  12. mercaptopurine
    drugsShowingFirstPassEffect.png

First pass metabolism occurs in the 📑gut for 📑 benzylpenicillin (penicillin G) and insulin and
in the liver for propranolol, lignocaine, chloromethiasole and GTN.

Phase 1 and phase 2 metabolism

Source

Phase 1: Oxidation, reduction and hydrolysis reactions - make the drug more polar and water soluble. Fa
Geriatric patients have reduced phase 1 reaction rates.
Phase 1 is catalyzed by the membrane-bound cytochrome P450.

Phase 2: glucuronidation, acetylation and sulfation - make a drug even more soluble by conjugation with another group.
Acetylation is one example. Patients can be slow or fast acetylators. [[Tuberculosis#Isoniazid]]

Phase 2 reactions occur on a metabolite formed by a phase I reaction that is still not adequately hydrophilic.
Phase II reactions result in the formation of readily excreted, less active,nontoxic substances.
They occur within hepatocytes cytoplasm.

Therapeutic index

$$ Therapeutic; index = \frac{LD_50}{ED_50} $$
LD50 = median lethal dose
ED50 = median effective dose

![Drugs narrow therapeutic window.png](Drugs narrow therapeutic window.png)

Digoxin

#2020SBR-NOV/Q03
Cardiac glycoside - Found in [[Plant toxins|Kaneru]]
Classified as Other in Vaughan Williams anriarrhythmic classification.
[[VaughanWilliamsClassificationAntiarrhythmics.png]]

Cardiac glycosides reversibly inhibit the sodium-potassium-ATPase, causing an increase in intracellular sodium and a decrease in intracellular potassium.

Indications and mechanism of action
Overall effects : increased contractile velocity (increased contractility) and decreased heart rate.

  1. Heart failure - inhibition of Na/K ATPase -> increased intra-myocyte sodium -> decreased Na calcium exchange -> reduced secretion of calcium -> increased intracellular calcium -> contractility increased.

In patients with HF, digoxin also inhibits sympathetic outflow and augments parasympathetic tone.

Antiarrhythmic - slows conduction through the AV node, increases vagal tone. This property is used to slow the ventricular rate in patients with persistent AF.

📑Avoid in acute coronary syndrome

[!INFO] Benign effects on the ECG:
Source
#2020GM-JUL/Q02
These effects occur at therapeutic doses

Is a water soluble drug (renally excreted) ?but has large volume of distribution - Distributed within skeletal and cardiac muscle. Patients with low muscle mass (elderly) or renal failure will need loading dose adjustment.
Drug has a large Vd. so it's makes sense that it exerts it's effects on muscle.

Digoxin toxicity

Factors predisposing to toxicity

Acute toxicity

Acute toxicity is uncommon: Effects are

Chronic toxicity

[!WARNING] Common effects of digoxin toxicity on the ECG
Other common dysrhythmias associated with digoxin toxicity include:

Management

Psychiatric drugs

See [[Psychiatric drugs]]

Anti-epileptic drugs

typesOfSeizures.pngSource
Focal seizure = previously called partial seizures.
Focal onset aware seizure = simple partial seizure = person doesn't lose awareness of surroundings.

Types of antiepileptic medications

#2020BSQ-JUL/Q22

Source + Bennet & Brown.

Antiepileptic drugs which may worsen seizures

These drugs, (among others) work by blocking sodium channels.
They show 'use dependence' whereby more frequently depolarizing neurons are affected more.

Lamotrigine

Is a substrate for inducible hepatic enzymes; dose must be increasedin pregnancy!!

Benzodiazepiens

are used for acute management of seizure. Not for seizure prophylaxis.
However, clonazepam is used to achieve rapid control of epilepsy. (eg. When a patient with frequent seizures presents for the first time).

Valproate

Special because it's useful for myoclonic, tonic clonic and absence seizures.
Low toxicity; Non sedative.
Multiple mechanisms of action:

Phenytoin metabolism and toxicity

[!TIP] Overview
Effective anti epileptic but with unpredictable pharmacology and significant toxic effects.

[!SUMMARY] Phenytoin
Phenytoin is a second line antiepileptic (now used mainly in ED settings) with narrow therapeutic window.
It has multiple side effects.

Mechanism:
Phenytoin binds to and inhibits voltage-dependent sodium channels, which are found on both neuronal and cardiac tissue.
Cardiac effect: shortens actions potentials and prolongs refractory period between them.`

Pharmacokinetics

#2020BSQ-NOV/Q15

pharmacodynamics

Enzyme inducer.

Interactions

Valproate displaces phenytoin from bound proteins -> increased risk of toxicity.
Ethanol / Phenobarbital

Clinical

Phenytoin toxicity

Symptoms : N/V, headache,
motor effects: nystagmus, tremor, cerebellar ataxia.
10 - 20 - occasional horizontal nystagmus
20 - 30 - nystagmus+
30 - 40 - ataxia, slurred speech, tremmors, NV
40 - 50 - lethargy, confusion and hyperactivity
> 50 mg/L. - Coma and seizures

IV phenytoin can have cardiac effects;
Rare side effect of IV phenytoin : purple glove syndrome: distal oedema of limbs with necrosis.

==Phenytoin worsens primary generalized epilepsies.==
📑Phenytoin worsens absence seizures and myoclonic seizures.

Management of phenytoin toxicity

Supportive; mortality rate is low.

Phenytoin side effects

Phenytoin Vs. Phenobarbitone

Phenytoin is structurally related to the barbiturates.

Antiepileptic drugs in pregnancy

Anticonvulsant hypersensitivity syndrome

New name is DRESS. "Drug reaction with eosinophilia and systemic symptoms.".
Occurs between 2 - 8 weeks after starting the drug.
Can occur with many drugs, including antiepileptics.
Features:

Management of status epilepticus

Rapid summary:

  1. Airway, breathing, circulation stabilization
  2. First dose of diazepam or lorazepam
  3. If not responding, second dose after 5 minutes
  4. Repeat a third dose of benzodiazepine.
  5. If not responding at 15 minutes, emergency neurology consultation
    1. Start IV fosphenytoin 5-10 of PE/kg (PE - phenytoin equivalents)
      1. Forphenytoin is the less cardiotoxic prodrug of phenytoin.
      2. Calculate the required phenytoin dose.
      3. Administer that number of "phenytoin equivalents";
      4. fosphenytoin-image-2-1.webpSource
    2. Prepare for ICU transfer
  6. If seizure continuing at 30 minutes, prepare for rapid sequence intubation and start midazolam infusion / propofol / phenobarbital.
  7. Titrate infusion.
    See UpToDate algorithm for details.

Prostaglandin and COX pathway

A Good overview of arachidonic acid metabolism in the context of mechanism of action of paracetamol <- lots of detail; too long to read in a hurry.

COX = cyclooxygenase

prostaglandinAndCyclooxygenase.png
PGHS = prostaglandin synthesae = cyclooxygenase

Cyclooxygenase (COX) is the rate-limiting enzyme in prostaglandin (PG) synthesis.
COX 1 = present in most tissues; "housekeeping". Protects the gastric mucosa, kidney function, platelet activation
COX 2 = usually expressed in brain, kidney and bone. During inflammation, it is expressed in other tissues as well.

The synthesized prostaglandins bind to G protein coupled receptors to exert their effects.

The graph shows the concentration of each drug needed to reduce activity of the COX 1 and 2 enzymes by 50% (IC50).

COX and fever

Fever occurs due to the induction of COX-2 and subsequent increase in PGE2.
Recently a COX-3 isoform has been discovered. It was shown to be more sensitive to inhibition by paracetamol than other COXes and, so, was thought to be the target of analgesic and antipyretic effect of paracetamol; but this has been disproved.

NSAIDS

NSAIDs have

Most NSAIDS inhibit COX-1 by competitive reversible inhibition.
COX-2 inhibition is usually irreversible.

The antiplatelet action of aspirin isn't seen with other NSAIDS.
NSAIDS other than aspirin tend to have deleterious cardiovascular effects: they can cause hypertension by interfering with macula densa function.

Paracetamol is an NSAID-like drug with antipyretic and analgesic properties but no antiinflammatory properties.

NSAIDS and renal injury

Kidney PGs are primarily local vasodilators.
In the setting of hypotension and reduced kidney perfusion from vasoconstriction stimulated by angiotensin II, norepinephrine, vasopressin, or endothelin, PG synthesis is increased to maintain kidney perfusion and minimize ischemia
PGs also increase renin secretion, antagonize the water-retentive effects of arginine vasopressin, and enhance sodium excretion (See "NSAIDs: Electrolyte complications")
NSAIDS can cause hyperkalemia, hyponatremia and oedema

Hemodynamically mediated AKI due to NSAIDs occurs via attenuation of PG-mediated renal vasodilation. In healthy patients, PGs play little role in renal hemodynamics.

NSAID comparison

Source - Katzung

Pharmacokinetics overview

[!INFO] Pharmacokinetics Vs. Pharmacodynamics
Dynamics = 'power'
Pharmacodynamics = effect drugs have on the body.
Pharmacokinetics = effect body has on drug concentrations.

Bioavailability

#2020BSQ-NOV/Q17

$$
Bioavailability=\frac{AUC_{oral}}{AUC_{IV}}
$$
where AUC = area under the curve for drug concentration Vs. time graph.
#2020BSQ-JUL/Q20

Calculating drug doses

Epic article by DeragedPhysiology
#2022BSQ Q17

Loading dose

Given when time-to-steady-state (4-5 half lives) would be too long to wait for the drug to take action.
$$Loading\space Dose = \frac{{Vd}\times{Tc}}{F}$$
Vd = volume of distribution, Tc = Target concentration, F = bioavailability

Dose rate and maintenance dose

For IV drugs given by infusion,

For drugs not given IV, these doses need to be divided by the bioavailability.

drugPharmacologyExamples.png

Half life:

The equation describing the half life of a drug:
$$
\large{C_t = C_0exp\frac{-CL_{tot}}{V_d}t}
$$
where 'exp' means e to the power of'.

alternative form
$$
\large{C_t = C_0.e^{-kt}}
$$

The elimination constant

The exponent part in the equation above is the elimination rate constant.
CLtot = total clearance (i.e plasma volume which contains the amount of drug removed by all systems in a unit time)

$$
\frac{-CL_{tot}}{V_d} = \text{elimination rate constant} = k_{el}
$$

[!INFO] Half life depends on clearance and volume of distribution
$$
half\space life = \frac{0.693}{K_{el}}
$$

Therapeutic index

$$
\Large{Therapeutic\space Index=\frac{LD_{50}}{ED_{50}}}
$$
Higher therapeutic index => less toxic drug (high LD or low ED)
Lower therapeutic index => more toxic drug (low LD or high ED)

Effect of #pregnancy on pharmacokinetics

#2020BSQ-NOV/Q15

Effect of liver failure on pharmacokinetics

Mathematics of hepatic pharmacokinetics

Source

[!INFO]
Extraction ratio : Hepatic extraction ratio ... is the fraction of the drug entering the liver in the blood which is irreversibly removed (extracted) during one pass of the blood through the liver.
$$
\large Extraction\space Ratio = \frac{C_{arterial} - C_{venous}}{C_{arterial}}
$$
Protein binding affects hepatic extraction ratio because hepatocytes have access only to the unbound form of the drug.
Therefore, the equation above is equivalently represented as
$$
\large E_H = \frac{fu\times Cl_{int}}{Q_{H}+fu\times Cl_{int}}
$$

  1. Hepatic blood flow
  2. Unbound fraction of the drug
  3. Intrinsic ability of the liver to metabolize the drug

[!INFO] The upshot
Drugs with low intrinsic clearance will have "intrinsic limited" clearance
Drugs with high intrinsic clearance will have "flow limited" clearance.
Extraction ratio for all drugs decreases with increasing hepatic flow.

Low extraction ratio drugs High extraction ratio drugs
Flow independent Flow dependent
Warfarin, phenytoin Morphine, GTN, propranolol, verapamil
Lignogaine

Effects in liver failure

In liver failure,

Chronic steroid use

Side effects

Synthetic corticosteroid Natural
Predni and Methyl predni
Dexamethasone
betamethasone
Triamcinolone
Little mineralocorticoid or andro/estrogenic activity
Therefore, they suppress HPA axis and Cause cushing
Mainly glucocorticoid activity
  1. HPA Axis - glucocorticoids suppress CRH and ACTH.
  2. Cushings

clinically desirable effects of steroids appear to result primarily from transrepression, which results in the decreased production of proinflammatory proteins

[!INFO] Glucocorticoids have non-genomic effects as well
"Nongenomic effects of glucocorticoids include rapid, nonspecific interactions of glucocorticoids with cellular membranes, nongenomic effects medicated by cytosolic glucocorticoid receptors, and specific interactions with membrane-bound glucocorticoid receptors"

[!INFO] Irriversible side effects
With the exception of cataracts, a potential acceleration in atherosclerotic vascular disease, and bone effects (osteoporosis and osteonecrosis), all glucocorticoid toxicity is at least partially reversible over time with glucocorticoid discontinuation

Other side effects of steroid

  1. Cushingoid features - Redistrubition of fat, coupled with weight gain due to increased appetite.
  2. Ophthalmologic effects - cataract (usually bilateral and distinct from age related cataract) and glaucoma and rarely exophtlamos
  3. Cardiovascular
    1. Fluid retention and hypertension - particularly at high doses.
    2. In healthy individuals, fluid retention is counteracted by "aldosterone escape mechanism". ( #2020BSQ-NOV/Q06)

      Pathologic Increase in aldosterone can cause salt and water retention. But after a few days (or about 3Kg gain in weight), diuresis occurs. This is in response to

      1. increased ANP secretion
      2. Pressure natriuresis - kidney decreases Na resorption in response to increased perfusion pressure
      3. Decreased DCT resorption of Na via downregulation of thiazide sensitive sodium chloride co-transporter. ^c2b35e
    3. Increased rate of progression of atherosclerosis and increased risk of ACS and stroke
    4. Increased risk of AF and Atrial flutter
  4. Gastric - ulcers, perforations, hepatic steatosis
  5. Bone - osteoporosis and osteonecrosis [[Hormone Physiology#Regulation of bone formation and resorption]]
    1. Glucocorticoids increase resorption and decrease formation by binding to receptors in the bone cells.
    2. Gut absorption of calcium is reduced, and urine calcium loss is increased.
      1. Can cause a secondary hyperparathyroidism.
  6. Myopathy - uncommon; painless proximal myopathy
  7. Neuropsychiatrics - mood disorders, psychosis, memory impairement
  8. Metabolic
    1. Hyperglycemia -
    2. including augmentation of hepatic gluconeogenesis, inhibition of glucose uptake in adipose tissue, and alteration of receptor and postreceptor functions
  9. Immune - predisposition to infection
  10. Haematologic - neutrophil leukocytosis <- decreased adhesion of neutrophils to the vessel walls. (?something to do with neutrophil rolling and adhesion in acute inflammation?)

Enzyme inducers and inhibitors

https://www.ncbi.nlm.nih.gov/books/NBK553990/table/ch31.Tab1/

https://associationofanaesthetists-publications.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2044.2005.04462.x

Methotrexate

Antifolate drug;
Absolute contraindications: pregnancy, breast feeding, alcoholism and alcoholic liver disease, any other type of chronic liver disease, leukopenia / thrombocytopaenia, anaemia, bone marrow hypoplasia.

Antiepileptic medications

Mechanisms of action

For some drugs, precise mechanism is unknown or several mechanisms are suspected.

See table in up to date

Alteration of sodium currents is the most common mechanism of action of available antiseizure medications.

Type of receptor blockade may explain why some drugs are more effective for particular types of seizures.

Phenytoin , phenobarbitone and carbamazepine are some of the oldest antiseizure medications. - Newer drugs have better pharmacokinetics.

Carbamazepine

Binds Na Channels

This binding extends the inactivated phase and inhibits the generation of rapid action potentials when the cell is experiencing incoming depolarizing trains

#TODO

Phenytoin and fosphenytoin

#2023SBR Q23

Fosphenytoin is the prodrug. Superceded Phenytoin for IV use. (? Not really in SL)
Block Na channels, like carbamazepine.
Inhibits synaptic transmission.
And others...

seizure types

focal and generalized seizures
for status epilepticus
and as a second-line agent for patients with mixed seizures

Pharmacology of Phenytoin

95% protein bound ; renal failure impairs protein binding.
Valproate is another highly protein bound drug which ?may displace Phenytoin and increase its plasma levels.

potent, broad spectrum CYP and glucuronidation inducer.

Side effects:
Systemic: gingival hypertrophy, body hair increase, rash, folic acid depletion, reduced bone density (enzyme induction -> incr. Vitamin D catabolism)

Stevens-Johnson / TEN (commoner in south Asia!)

[!INFO] Ataxia
"ataxia" - disordered

Neurologic :
confusion
Slurred speech, ataxia, diplopia (all involving the head region)
Neuropathy

Phenobarbital / Phenobarbitone

Enzyme inducers and inhibitors

[!TIP] left Side - Inhibitors; Right side - INDUCERS,

Strong inhibitors Strong inducers
Clarithromycin Carbamazepine
Itrakonazole, ketoconazole Phenytoin
Voriconazole Fosphenytoin
Phenobarbital
Rifampicin
Moderate inhibitors Moderate inducers
Amiodarone Bosentan
Aprepitant/ fosaprepitatnt Dexamethasone
Cimetidine St. John's wort
Diltazem
Erythromycin
Fluconazole
Verapamil

Protein bound drugs

The protein bound from and free form of drugs are in equilibrium. The bound form acts as a reservoir. The unbound form is active and also subject to elimination.
ProteinBinding.png
The free, unbound portion of a drug can be very small. (1%).
The most important protein which binds drugs is albumin.
Albumin binds many acidic drugs - warfarin, NSAIDS, Sulfonamides.
and fewer basic drugs (TCA, chlropromazine).

DrugsAffectedByProteinLevel.png

For most drugs at therapeutic concentration, the carrier proteins are very far from saturated.
At these concentrations, bound fraction does not changes with drug concentration.

However, tolbutamide almost completely saturates proteins at therapeutic level. So increasing dose increases the free proportion disproporionately. (Tolbultamide is a nonantimicrobial sulfonamide)

Sulfonamides have very high affinity so they occupy about 50% of the binding sites on albumin. This allows sulfonamides to significantly displace other protein bound drugs.

From DerangedPhysiology:

Selected drugs which are highly protein bound
Source

  1. Phenytoin [[#Phenytoin toxicity]]
  2. Warfarin
  3. Levothyroxine
  4. Ibuprofen, indomethacin,
  5. Tolbutamid - contains a sulfa group
  6. Acetazolamide
  7. Amiodarone

Sulfonamides / sulphonamides

sulfonamideGroup.png

Initially developed as antibacterials; not used much now for that role (because of resistance) except for

  1. sulfamethoxazole (given in combination with trimethoprim as co-trimoxazole, i.e TMP-SMX) -> Pneumocystis jirovecii infection, Stenorophomonas
  2. Sulfasalazine (poor GI absorption - used for UC and crohn's)
  3. Silver sulfadiazine

Non antibacterial sulfonamides

  1. prasugrel
  2. acetazolamide
  3. Celecoxib and some other COX-2 inhibitors

There are antimicrobial and non antimicrobial sulfonamides: There's a large list!
List

Sulfonamide-containing nonantimicrobial agents (Table 1) include agents from therapeutic classifications such as thiazide and loop diuretics, carbonic anhydrase inhibitors, nonsteroidal anti-inflammatory drugs, sulfonylureas, antiretrovirals, and 5HT-3 receptor agonists

In the general population, approximately 3–8% of patients are reported to experience a sulfonamide allergy.
Stevens-Johnson syndrome can occur.

[!INFO] Allergy
Although many types of drugs have the NH2-SO2 sulpha group and are therefore technically 'sulfa-drugs', they don't have some additional group which are responsible for the allergies caused by the antibacterial sulphonamides. Therefore, cross reactivity and allergy risk is low.

The nonantimicrobial sulfonamides do not undergo metabolism to the N4-hydroxylated metabolite associated with SJS and will not bind to IgE at the N1 position and, therefore, are unlikely to cause cross-reactivity, even in patients who have experienced type 1 hypersensitivity or serious non-type-1 hypersensitivity reactions to sulfonamide antimicrobial agents.

Drugs Showing Zero order kinetics

#2020BSQ-JUL/Q19
📑 A few known drugs show zero order / 0 order kinetics.
==Most drugs show first order kinetics==.
ChatGPT: (verified)

  1. 📑Aspirin - At high doses. Low doses -> first order.
  2. Phenytoin
  3. Ethanol
  4. Salicylates other than aspirin (sodium salicylate)
  5. 📑 Lithium
  6. Procainamide
  7. 📑 Omeprazole
  8. 📑 fluoxetine
  9. cisplatin

Important implications for saturation kinetics:

Illustration of the difference of variation in plasma concentration between zero and first order kinetics:
zeroOrderVsFirstOrderKinetics.png

Phenytoin is the classical poster child for non-linear elimination kinetics, because the enzyme saturation point is reached somewhere in the middle of the therapeutic concentration range - Deranged Physiology

Efficacy and potency

#2018BSQ-OCT/Q02
Efficacy is the maximum effect that a drug can exert.
Potency is the concentration/dose of drug required to exert 50% of it's maximal effect.
Source

Efficacy:

efficacy.jpg
A has higher efficacy than B.
But the dose at which 50% of maximum drug effect is achieved for Both A and B are similar. (?so similar potency?)

Therapeutic efficacy and pharmacological efficacy

The concept above is therapeutic efficacy.
Pharmacological efficay (also called Intrinsic efficacy) is

is the drug's maximal efficacy as a fraction of the maximal efficacy produced by a full agonist of the same type acting through the same receptors under the same conditions

Potency

potency.jpg
A and B have the same maximum effect (i.e same efficacy) but A achieves this at a lower dose; Therefore, A is more potent.

![efficacy and potency.jpg](efficacy and potency.jpg)

Drug B is more potent than Drug A. Drug A and B have the same efficacy.
However, A has a steeper dose response curve so it requires a smaller increase in dose than B to achieve maximum effect.

Calcium channel blockers

#2022SBR-MAY Q08
calciumChannelBlockers.png

[!TIP] Dihydropyridines end with 'pine'

Calcium channel blockers block the voltage gated L type calcium channels on cells, inhibiting calcium entry.
They show 'use dependence' so that they most affected tissues are heart and smooth muscle.

In smooth muscle, they cause relaxation -> predominant clinical effect is arteriolar dilation and coronary artery dilation; lowers blood pressure but also causes oedema.

In the heart, they have delay conduction and have a negative inotropic effect.

Site of action:
Most dihydropyridines affect smooth muscles more than the heart.
Ditiazem (nondihydropyridine) has intermediate action.
Verapamil acts mainly on the heart.

[!INFO] Specificity of heart Vs. smooth muscle lies along a spectrum

Side effects are extensions of the pharmacological action.
Hyperglycemia is a side effect of CCB overdose which helps differentiate this from beta blocker overdose.

Toxic shock syndrome

#2022SBR-MAY Q14

Caused by TSST-1 toxin produced by staph aureus.
Toxin causes cytokine release which leads to rapid (48 hr) development of clinical features:

Treatment:

  1. Treat shock
  2. Source control - i.e wound exploration
  3. Antibiotics - antistaphylococcal antibiotic (carbapenem or penicillin + beta lactamase inhibitor) AND clindamycin to suppress toxin production.

Staphylococcal scalded skin syndrome

Occurs in children < 5 years old.
Exfoliatin produced by Staph aureus causes intrapidermal separation of the skin (at level of stratum corneum) resulting in flaccid blisters. Benign condition. Only requires flucloxacillin.


[!INFO] Mast cells


Henoch Schonlein purpura

Previously called IgA vasculitis.


False negative False positive
Incorrect technique TB infection (but not disease)
Immunosuppression (HIV, lymphoma, late CKD) Past disease
viral infections Non tuberculous mycobacteria
Malnutrition
Vaccination with live viral vaccine
Sarcoidosis (sarcoid. granulomas interfere)
Miliary TB (due to anergy)

Diagnosis of active TB


We are concerned with the true positive rate and true negative rate of a test.

[!INFO] interpretation of sensitivity and specificity
SNOUT and SPINS

Type 1 and type 2 errors

This part is intuitive:

[!INFO] Type 1 Vs type 2 error

[!INFO] prerequisite knowledge:

TypesOfStatisticalTests.jpeg

t-tests

Assumptions made with regards to independent samples t-tests

Levels of measurement

Nominal = categorial
No sense of order.
Frequency or percentage is used to summarise.

Ordinal:
Have an order.
But the interval between values is unequal.

Interval / ratio
Things that can be measured

Power of a study

The probability that a study will detect a difference in measurement between two groups when such a difference actually exists, given a pre-set p alpha and sample size.


phaeochromocytomaClinicalAspects.png

Metabolic alkalosis

Source
metabolicAlkalosisCausespathogenesis.png

Chloride responsive Chloride resistant
GI H+ loss HCO3- retention
contraction alkalosis Intracellular H+ shift
Diuretic therapy Hyperaldosteronism
Post hypercapnia Barter syndrome
Cystic fibrosis Gitelman syndrome
Exogenous alkalotic

[!INFO] Pendrin
Is a key transport protein involved in pathogenesis.

"internal potassium balance".

The transcellular shifts in K+ caused by acid base changes.
Basis: In acidosis, about half the H+ is buffered intracellularly. To maintain electroneutrality, intracellular K+ moves outwards into the ECF.

[!INFO] Hypoaldosteronism
In patients with hypoaldosteronism, for example, the mild metabolic acidosis is primarily due to the associated hyperkalemia
UpToDate

Familiar mediterranean fever